tbuckley/cabot-search huggingface dataset:
Health-related quality of life (HRQoL) and pain in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Dana E. Rathkopf, Guilhem Roubaud, Kim N. Chi, Shahneen Sandhu, Eleni Efstathiou, Gerhardt Attard, David Olmos, Ji Youl Lee, Eric Jay Small, Andrea Juliana Gomes, Marniza Saad, Elena Castro, Deniz Tural, Gary Mason, Katherine B. Bevans, Jeremiah Trudeau, Peter St. John Francis, George C. Wang, Angela Lopez-Gitlitz, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2022)

5060 Background: Results from the international, randomized, double-blind, phase 3 MAGNITUDE study demonstrated that NIRA + AAP improved radiographic progression-free survival, time to cytotoxic chemotherapy, and time to symptomatic progression, with manageable toxicity in pts with mCRPC and HRR alterations (9-gene panel). Here, we report HRQoL and pain in MAGNITUDE. Methods: Eligible pts with mCRPC and HRR alterations were randomized 1:1 to NIRA + AAP or placebo (PBO) + AAP orally daily in 28-day cycles. Pts had ECOG status ≤1 and a Brief Pain Inventory–Short Form (BPI-SF) worst pain score ≤3 in prescreening. HRQoL assessments on day 1 of specified cycles included Functional Assessment of Cancer Therapy–Prostate (FACT-P) and BPI-SF. Changes from baseline were compared between treatment arms using repeated measures analysis. Proportional hazards regression models were used to compare time to deterioration (TTD) in worst pain intensity between arms. Results: Compliance for FACT-P and BPI-SF was &gt; 80%. Most pts maintained low pain levels over time. Repeated measures analyses showed no clinically meaningful differences in pain over time or between arms. Median TTD in pain intensity was not reached in either arm. At the 25th percentile, there was a trend toward longer TTD in pain intensity with NIRA + AAP vs PBO + AAP (11.1 vs 10.1 mo; HR, 0.87; 95% CI, 0.61-1.24). HRQoL was maintained with NIRA + AAP, with no clinically meaningful differences in FACT-P total score over time or between arms. There was a trend toward greater worsening in early cycles on FACT-P physical wellbeing with NIRA + AAP vs PBO + AAP, driven by events within the known safety profile of NIRA + AAP (worsening of side effect bother, lack of energy, and nausea); however, overall, most pts reported minimal side effect burden (Table). Conclusions: In MAGNITUDE, most pts maintained low pain levels and positive HRQoL over time, with no clinically meaningful differences between treatment arms, further supporting the use of NIRA + AAP in pts with mCRPC and HRR alterations. Side effect burden was perceived as low in both arms. Although more pts on NIRA+AAP reported worsening side effects, the symptoms were generally perceived as mild. Clinical trial information: NCT03748641. [Table: see text]
Association of <i>RB1</i> mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).
Authors: Petros Grivas, Gennady Bratslavsky, Joseph M Jacob, Oleksandr Kravtsov, Andrea Necchi, Philippe E. Spiess, David R Wise, Natalie Danziger, Vamsi Parimi, Ethan Sokol, Hanna Tukachinsky, Mia Alyce Levy, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2022)

5063 Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC in RB1 mutated vs non-mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, we identified 415 cases (3.1%) with a diagnosis of small cell PC or NEPC as determined by the submitting physician. They were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P &lt;.0001). The RB1 mut+ NEPC featured a slightly greater number of pathogenic GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were uncommon in both groups. gLOH was higher in RB1 mut+ than RB1 mut- (P =.005). There were more cases of non-European ancestry in the RB1 mut- group. APC I1307K mut were found in 3/162 (1.9%) RB1 mut- NEPC only. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Further study of RB1 status as a guide in trial designs on therapy selection for men with NEPC appears warranted. [Table: see text]
<i>PAPPA2</i> mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC and SKCM.
Authors: Yiting Dong, Zhijie Wang, Jie Wang, Jianchun Duan, Hua Bai, Lele Zhao, Dong-sheng Chen, Si Li, Yangyang Yu, Qin Zhang, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

2617 Background: Pappalysin 2 ( PAPPA2) mutation, most occurring in skin cutaneous melanoma (SKCM) and non-small cell lung cancer (NSCLC), is found to be related to anti-tumor immune response. However, the association between PAPPA2 and efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. Methods: Forty-one NSCLC patients receiving anti-PD-(L)1 (China cohort, n = 41) and seven public cohorts with whole-exome sequencing (WES) data were included to analyze the performance of PAPPA2 mutation as an indicator stratifying patients benefit from ICIs, consolidating a discovery set (n = 34) and two validation sets (NSCLC validation set, n = 172 ; SKCM validation set, n = 210). The mechanism was analyzed in the Cancer Genome Atlas (TCGA) database (n = 1467). Results: In the discovery set, patients with PAPPA2 mutation exhibited a significantly predominant PFS (HR, 0.11 [95% CI, 0.01-0.83]; P = 0.01), ORR (100.0% vs 21.4%; P &lt; 0.001) and durable clinical benefit (DCB, 83.3% vs 32.1%; P = 0.012) compared to those with wide-type PAPPA2, consistent in NSCLC validation set (PFS, HR, 0.3 [95% CI: 0.16-0.56], P &lt; 0.001; ORR, 70.8% vs. 20.9%, P &lt; 0.001; DCB, 83.3% vs. 36.5%, P &lt; 0.001) and SKCM validation set (OS, HR, 0.49 [95% CI: 0.31-0.78]; P = 0.002; ORR, 34.1% vs. 16.9%, P = 0.039; DCB, 50.0% vs. 30.7%; P = 0.036). Similar results were observed in multivariable models. In contrast, no association between PAPPA2 mutation and OS or PFS was observed in TCGA datasets, suggesting that PAPPA2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, we found that PAPPA2 mutation was significantly associated with higher activated CD4 memory T cells and lower Treg cells in tumor immune microenvironment, related with higher TMB ( P &lt; 0.001) and neoantigen load ( P &lt; 0.001). In addition, gene set enrichment analysis (GSEA) analysis revealed that PAPPA2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway. Conclusions: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies.
Access to care in patients with pancreatic adenocarcinoma by race/ethnicity in an academic center in the Bronx, NY.
Authors: Michael Brodsky, John X Wei, Francesco Castagna, Erin Jou, Michael Shusterman, Sanjay Goel, Ana Acuna-Villaorduna
Journal: Journal of Clinical Oncology (2022)

e16280 Background: Racial disparities in the overall survival (OS) of patients with pancreatic adenocarcinoma (PDAC) have been previously reported. Large population datasets suggest that Non-Hispanic Blacks (NHB) have decreased OS when compared to non-Hispanic Whites (NHW), and Hispanics. It is unclear whether this is related to biologic features or differences in access to care. This study was aimed to compare time to treatment in a racially-diverse cohort of patients with PDAC in an academic center in the Bronx, NY. Methods: Patients diagnosed with PDAC between 2015 and 2021, available race/ethnicity (NHW, NHB or Hispanic) who received treatment at Montefiore Medical Center were identified. Data including demographics (age, gender, BMI), clinical features (date of diagnosis, presentation [localized/metastatic], tumor location, grade), first-treatment received (surgery or chemotherapy) and outcomes (vital status, date of death) were collected manually. Time to first treatment was compared between racial/ethnic groups using the Kruskal-Wallis test. Results: Of 226 patients diagnosed with PDAC, there were 46 (20.4%), 77 (34.1%) and 103 (45.6%) NHW, NHB and Hispanics respectively. The frequency of metastatic disease was higher in Hispanics and NHB compared to NHW (42.7% vs. 46.7% vs. 22.2%, p = 0.02). Median time to first treatment did not differ significantly among racial/ethnic groups in the overall cohort and stratified by disease presentation. Conclusions: There were no differences in access to care among racial/ethnic groups in this cohort. A higher frequency of metastatic disease at presentation among NHB and Hispanics might be explained by more aggressive biology. Further evaluation of the molecular profile in this cohort is warranted.[Table: see text]
Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UCB) genomic alteration (GA) profile.
Authors: Andrea Necchi, Petros Grivas, Philippe E. Spiess, Gennady Bratslavsky, Joseph M Jacob, Oleksandr Kravtsov, Richard S.P. Huang, Ryon Graf, Natalie Danziger, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2022)

e16535 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been used as a biomarker to predict immune checkpoint inhibitors response in UCB. We hypothesized that the GA profiles would differ between UCB featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UCB with known PD-L1 tumor cell expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alteration (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included in this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UCB featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amplification (P = .05). The gender, age and GA per tumor frequencies were similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p = .02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. The mean gLOH scores were similar in both groups. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UCB cases where a mutational signature could be determined, 15/33 (45%) of PD-L1H and 34/112 (30%, p = 0.14) of PD-L1N UCB featured an APOBEC gene signature; 79% of PD-L1H and 83% of PD-L1N featured European ancestry (p = 0.61). Conclusions: PD-L1H and PD-L1N subtypes of UCB differ in their genomic profiles. PD-L1N UCB features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UCB but also in designing trials that may combine ICPI with targeted therapies.[Table: see text]
Increase in incidence of advanced-stage breast cancer in Asian women versus White women: Can this be explained by the lower utilization of mammograms?
Authors: Cheng-I Liao, Michelle Ann P. Caesar, Danny Lee, Chloe Chan, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2022)

10524 Background: To examine trends in postmenopausal breast cancer and mammogram utilization in Asian and White women in the United States. Methods: Data on postmenopausal breast cancer was obtained from the United States Cancer Statistics Public Use Database from 2001 and 2018. Rates of mammogram screening for women ages 18 and older were evaluated using the Behavioral Risk Factor Surveillance System (BRFSS) between 2000 and 2018. Obesity rates for women ages 18 and older were extracted from BRFSS between 2001 and 2016. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate incidence trends. Breast cancer incidence and trends were described using average annual percent change (AAPC). Mammogram screening trends were described using average biennial percent change (ABPC). Obesity trends were described using AAPC. Age groups were divided into five-year or ten-year intervals. Results: The incidence of metastatic postmenopausal breast cancer in women was 19.48/100,000 in 2018 has increased by 1.03% annually over the past eighteen years (p = 0.000). In 2018, the incidence of advanced-stage breast cancer in Asian and White women was 12.17/100,000 and 19.17/100,000 respectively. Over time, the incidence of advanced-stage breast cancer has increased in Asian women by 2.19% annually (p = 0.000), but remained stable in White women. In a subset analysis of early-stage breast cancer, there was no difference in both Asian and White women. Using the BRFSS data, we evaluated the utilization of mammograms. In the overall population, 20.92% were newer screened and this was higher in Asian women at 40.99% compared to 18.17% in White women in the year 2018. Given the potential association of obesity and breast cancer, we then evaluated the rate of obesity in these two groups. Our data showed that the incidence of obesity was low in Asian women at 12.8% compared to 28.13% in White women. Conclusions: There is an increased incidence of advanced-stage breast cancer in Asian women in the U.S. Although Asian women are less obese but they are also less likely to undergo screening compared to White women.
Phase II, double-blind, randomized study of salvage radiation therapy (SRT) plus enzalutamide or placebo for high-risk PSA-recurrent prostate cancer after radical prostatectomy: The SALV-ENZA Trial.
Authors: Phuoc T. Tran, Kathryn Lowe, Hao Wang, Hua-Ling Tsai, Daniel Y. Song, Arthur Hung, Jason W.D. Hearn, Tamara L. Lotan, Channing Judith Paller, Mark Christopher Markowski, Samuel R. Denmeade, Michael Anthony Carducci, Mario A. Eisenberger, Matthew Orton, Curtiland Deville, Stanley L. Liauw, Elisabeth I. Heath, Neil B Desai, Tomasz M. Beer, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2022)

5012 Background: We sought to investigate whether enzalutamide (ENZA) treatment, without androgen deprivation therapy, increases freedom-from-PSA-progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer post-radical prostatectomy (RP). Methods: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT + placebo vs SRT + ENZA. The randomization (1:1) was stratified by center, surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs &lt; 0.5 ng/mL), and pathologic Gleason sum (7 vs 8-10) using a minimization algorithm. Following randomization, patients received either placebo or ENZA 160 mg PO once daily for 6 months. Following 2 months of study drug therapy, external beam radiotherapy to 66.6-70.2 Gy was administered to the prostate bed (no pelvic nodes). The primary endpoint was FFPP. The trial design was powered for a HR 0.44 FFPP benefit with intended enrollment of 96 subjects and was closed as planned to enrollment on March 2020 short of that goal. Secondary endpoints were time to local recurrence (LR) within the radiation field, metastasis‐free survival (MFS), and safety as determined by frequency and severity of adverse events (AEs). Results: A total of 86 patients were randomized with a median follow-up of 34 (range 0-52) months. The median pre-SRT PSA was 0.3 (range 0.06-4.6) ng/mL, 56/86 (65%) had extra-prostatic disease (pT3), 39/86 (45%) had Gleason Grade Group 4 or higher and 43/96 (50%) had positive surgical margins. Trial arms were well balanced. FFPP was significantly improved with ENZA vs placebo, for example 2-year FFPP was 87.1% vs 68.1%, respectively, and overall with a HR 0.40 [95% confidence interval (CI), 0.17-0.92, p-value = 0.026]. Subgroup analyses demonstrate differential benefit (p-value of interaction = 0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs pT2 disease (HR 1.29, 95%CI 0.34-4.81). There were insufficient secondary endpoint events for analysis. The most common adverse events were grade 1-2 fatigue (13% ENZA vs 9%) and urinary frequency (6 % ENZA vs 8%). Conclusions: SRT plus ENZA monotherapy for men with PSA recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time. Additional molecular biomarker analyses are being pursued. Clinical trial information: NCT02203695.
Mechanisms of anticancer activity of bacteria in enhancing cancer immunotherapy.
Authors: Sin-Hyeog Im, Garima Sharma, Amit Sharma, Inhae Kim, Soo-Woong Lee, Hye-Na Lee, ChangWook Park, Dipayan Rudra
Journal: Journal of Clinical Oncology (2022)

e15047 Background: Numerous studies indicate that selective microbiota could enhance anti-tumor immunity with checkpoint inhibitors. However, it is arduous to identify the best candidate bacteria strains and understand their underlying action mechanisms. Methods: We have developed Avatiome platform technology, an innovative pre-clinical model system that mimics the human body's immune system and microbiome. Avatiome incorporates up-to-date technologies such as immunophenotyping, single-cell transcriptomics, and an Artificial Intelligence system to develop novel therapeutics targeting neuronal, systemic inflammatory diseases, and cancers. Results: We have identified Lp IMB19 as an LBP candidate that can enhance anti-cancer immunity through this technology. Lp IMB19 suppresses tumor progression in pre-clinical models of melanoma, renal cancer, and NSCLC. Lp IMB19 efficiently potentiates the therapeutic effect of anti-PD-L1 in murine tumor models by enhancing the effector function of CD8 + T cells via altering the phenotypes of tumor-infiltrating macrophages with inflammatory M1 type. We have identified rhamnose-rich heteropolysaccharides (RHP) as key effector molecules to induce M1 macrophage in a TLR2 dependent manner. Lp IMB19 also limits the amount of iron availability via Lipocalin 2 (LCN2) to capture trace iron from the microenvironment and switch to an iron sequestration phenotype, subsequently inhibiting tumor growth. No side effect or toxicity is observed in pre-clinical toxicity studies. Conclusions: We are currently developing Lp IMB19 as an onco-biotics for clinical investigation as a live biotherapeutic product (LBP) combined with immune checkpoint inhibitors.
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting multifunctional immune-recruitment protein, in patients with advanced solid tumors.
Authors: Jason J. Luke, Anwaar Saeed, Babar Bashir, Yaffa Shwartz, Rinat Tabakman, Adam Foley-Comer, Antonio Jimeno
Journal: Journal of Clinical Oncology (2022)

2647 Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.